Pharmaceutical formulations for the treatment of dry eye and methods for fabricating and using thereof

ABSTRACT

Methods and kits for improving tear production are described, along with topical pharmaceutical compositions. In certain instances the composition comprises pentoxifylline and a pharmaceutically acceptable carrier. The compositions also may further comprise another active agent, such as an anti-bacterial agent, antiviral agent, antifungal agent, or immunosuppressant agent, and combinations thereof.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Ser. No. 62/711,862, filed Jul. 30, 2018, the entire content ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to the field of ophthalmologyand more specifically to compositions and methods designed to treat,mitigate or prevent dry eye syndrome in mammals, and to methods ofpreparing such compositions.

BACKGROUND

Dry eye is an ocular disease that results in symptoms of discomfort andvisual disturbance as a result of decreased tear production, and ischaracterized by a dysfunction of one or more components of the tearfilm, the latter being stable in the absence of this disease. Teardeficiency may be caused by poor production of tears as a result of age,hormonal changes, various autoimmune diseases and other factors, and maybe also a side effect of certain medications, such as beta-blockers,antidepressants, antihistamines etc. However, normal stable condition ofthe tear film resulting in normal tear secretion is important for thelubrication and maintenance of the refractive surface of the eye.

Dry eye may afflict an individual with varying degrees of severity,ranging from burning sensation, a feeling of dryness and persistentirritation up to substantial impairment of vision in more severe cases,vision may be substantially impaired. Therefore, a variety of approacheshave been developed for treatment and therapy. Typically the majority ofpatients with dry eye syndrome are prescribed or recommended artificialtears. Other methods and devices that are also often recommended includescrubs, drops, inserts, plugs or lid compresses. These productstypically comprise immunologic agents, autologous compounded serum,mucin producing agents or lubricants. While some such remedies do existand may provide some relief in some cases, in many other instances theyare insufficient or too expensive. Accordingly, it is desirable to havebetter alternative compositions.

This patent specification discloses such pharmaceutical compositionssuitable for treatment and alleviation of dry eye disease that canachieve positive patient outcomes while free of drawbacks anddeficiencies of existing formulations, and methods of fabricating andadministering the same.

SUMMARY

According to one embodiment of the invention, a method for improvingtear production in a mammalian subject suffering from insufficientsecretion thereof is provided. The method includes administering to thesubject a pharmaceutical formulation comprising a therapeuticallyeffective amount of a compound of formula I:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein each of R¹, R² and R³ is H, a C₁-C₆ alkyl, a C₂-C₆ alkenyl, aC₂-C₆ alkynyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl,each of which is further optionally substituted.

According to another embodiment of the invention, the compound offormula I shown above is pentoxifylline.

According to yet another embodiment of the invention, the methodsdisclosed herein are useful for treating the insufficient tear secretionthat is caused by a disease, syndrome or pathology such askeratoconjunctivitis sicca, Stevens-Johnson syndrome, age-related dryeye, ocular cicatricial pemphigoid, neurotrophic ocular surface diseaseand/or blepharitis.

According to other embodiments of the invention, the pharmaceuticalcompositions described herein may be delivered topically, e.g., can beformulated and delivered to a patient as eye drops.

DETAILED DESCRIPTION A. Terms and Definitions

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques ofanalytical chemistry, synthetic organic and inorganic chemistrydescribed herein, are those known in the art. Standard chemical symbolsare used interchangeably with the full names represented by suchsymbols. Thus, for example, the terms “hydrogen” and “H” are understoodto have identical meaning. Standard techniques may be used for chemicalsyntheses, chemical analyses, formulating compositions and testing them.The foregoing techniques and procedures can be generally performedaccording to conventional methods well known in the art.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“includes,” and “included,” is not limiting.

“About” as used herein means that a number referred to as “about”comprises the recited number plus or minus 1-10% of that recited number.For example, “about” 100 degrees can mean 95-105 degrees or as few as99-101 degrees depending on the context. Whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange; i.e., meaning only 1, only 2, only 3, etc., up to and includingonly 20.

The term “pharmaceutical composition” is defined as a chemical orbiological compound or substance, or a mixture or combination of two ormore such compounds or substances, intended for use in the medicaldiagnosis, cure, treatment, or prevention of disease or pathology.

The term “dry eye” or “dry eye syndrome” is defined as one or severalconditions associated with, or caused by, either decreased tearproduction or increased tear film evaporation, or both, andcharacterized by redness, itching, and burning of the eye. Dry eyesyndrome is inclusive of keratoconjunctivitis sicca.

The terms “anti-bacterial” and “antibiotic” used herein interchangeably,refer to any substance or compound that destroy bacteria and/or inhibitthe growth thereof via any mechanism or route.

The term “anti-viral” refers to any substance or compound thatcounteract or suppress any viral substance via any mechanism or route.

The term “immunosuppressant” refers to any substance or compound thatcan suppress, reduce or prevent the immune response.

The term “tumor necrosis factor” refers to any protein that is capableof inducing death of tumor cells; accordingly, a tumor necrosis factor“antagonist” or “inhibitor” refers to any compound or substance that iscapable of counteracting of a tumor necrosis factor or suppressing,diminishing or reducing body's response to it.

The term “salt” refers to an ionic compound which is a product of theneutralization reaction of an acid and a base.

The terms “solvate” and “hydrate” are used herein to indicate that acompound or substance is physically or chemically associated with asolvent for “solvates” such as water (for “hydrates”).

The term “carrier” refers to a substance that serves as a vehicle forimproving the efficiency of delivery and the effectiveness of apharmaceutical composition.

The term “excipient” refers to a pharmacologically inactive substancethat is formulated in combination with the pharmacologically activeingredient of pharmaceutical composition and is inclusive of bulkingagents, fillers, diluents and products used for facilitating drugabsorption or solubility or for other pharmacokinetic considerations.

The term “therapeutically effective amount” is defined as the amount ofthe compound or pharmaceutical composition that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, medical doctor or other clinician.

The term “pharmaceutically acceptable” when used to describe a carrier,whether diluent or excipient, refers to a substance that is compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof.

The terms “administration of a composition” or “administering acomposition” is defined to include an act of providing a compound of theinvention or pharmaceutical composition to the subject in need oftreatment.

B. Embodiments of the Invention

According to embodiments of the present invention, methods for improvingtear production in a mammalian subject suffering from insufficientsecretion thereof are provided. The methods include administering to thesubject a pharmaceutical formulation comprising a therapeuticallyeffective amount of a tumor necrosis factor antagonist or inhibitor(TNF) such as a compound of formula I:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein each of R¹, R² and R³ is H, a C₁-C₆ alkyl, a C₂-C₆ alkenyl, aC₂-C₆ alkynyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl,each of which is further optionally substituted. The composition mayinclude a single compound of formula I or a combination of several suchcompounds each of which is described by formula I. The quantity ofcompound of formula I in the pharmaceutical formulation expressed asmolar concentration can be between about 0.03 mM and about 3 mM ofcompound of formula I per 1 μL of the entire formulation.

In one embodiment the compound of formula I is pentoxifylline, i.e.,1-(5-oxohexyl)-3, 7-dimethylxanthine, a compound of formula I where eachof R² and R³ is methyl and R¹ is 5-oxohehyl, i.e., a functional grouphaving the structure —(CH₂)₄—C(O)—CH₃. Lisofylline, an active metaboliteof pentoxifylline, i.e.,1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dimethylxanthine can be also used ifdesired. The structure of lisofylline is basically the same as that ofpentoxifylline except its functional group R¹ includes a primary alcoholmoiety —C(OH)— instead of the acyl moiety —C(O)— that is present in theR¹ group in pentoxifylline. Other non-limiting examples of compoundsencompassed by formula I that can be used include aminophylline,enprofylline and isbufylline.

The pharmaceutical formulations that are described herein may inaddition optionally contain other pharmacologically active compoundssuch as at least one anti-bacterial agent(s), at least one antiviralmedicament(s), at least one antifungal medicament(s), at least oneimmunosuppressant(s) and combinations thereof. Those having ordinaryskill in the art can determine what specific anti-bacterial, antiviral,antifungal medicament(s) and/or immunosuppressant(s) are to be used, ifany.

In various embodiments, the concentration of the anti-bacterial agent(s)in the ophthalmological compositions of the present application may bebetween about 0.0 mg/mL and about 50.0 mg/mL, such as between about 0.5mg/mL and about 10.0 mg/mL, for example, about 1.0 mg/mL. Non-limitingexamples of the anti-bacterial agents that may be used includefluoroquinolones such as moxifloxacin, gatifloxacin, nalidixic acid,oxolinic acid, piromidic acid, pipemidic acid, rosoxacin, enoxacin,fleroxacin, lomefloxacin, nadifloxacin, ofloxacin, pefloxacin,rufloxacin, balofloxacin, levofloxacin, norfloxacin, ciprofloxacin,pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gemifloxacin,sitafloxacin, prulifloxacin and combinations thereof.

Non-limiting examples of anti-bacterial agents other thanfluoroquinolones that may be used include vancomycin, teicoplanin,telavancin, decaplanin, ramoplanin, azitromycin, gentamicin, tobramycin,amikacin, cefuroxime, mitomycin, neomycin, neosporin, amoebicides (e.g.,metronidazole, tinidazole, secnidazole, orornidazole, polyhexamethylenebiguanide or chlorohexidine), polymyxin, clindamycin, bacitracin,chloramphenicol, erythromycin, natamycin, blephamide, sulfacetamide,sodium bicarbonate, povidone-iodine and combinations thereof.

In various embodiments, the concentration of the antiviral medicament(s)in the ophthalmological compositions of the present application may bebetween about 0.01 mg/mL and about 75.0 mg/mL, such as between about 1.0mg/mL and about 50.0 mg/mL, for example, about 20.0 mg/mL. Non-limitingexamples of the antiviral medicaments that may be used includeidoxuridine, vidarabine and combinations thereof.

In various embodiments, the concentration of the antifungalmedicament(s) in the ophthalmological compositions of the presentapplication may be between about 0.01 mg/mL and about 75.0 mg/mL, suchas between about 1.0 mg/mL and about 50.0 mg/mL, for example, about 20.0mg/mL. Non-limiting examples of the antifungal medicaments that may beused are ketoconazole and fluconazole.

In various embodiments, the concentration of the immunosuppressant(s) inthe ophthalmological compositions of the present application may bebetween about 0.01 mg/mL and about 50.0 mg/mL, such as between about 0.1mg/mL and about 30.0 mg/mL, for example, about 20.0 mg/mL. Non-limitingexamples of the immunosuppressants that may be used include tacrolimus,cyclosporine and combinations thereof.

As mentioned above, the pharmaceutical composition that is the subjectmatter of the instant application may further optionally include one orseveral pharmaceutically acceptable excipient(s). In some embodiments,an excipient that can be used may be a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followinggeneral structure:HO—(CH₂—CH₂—O)_(x)—(C₃H₆—O)_(y)—(CH₂—CH₂—O)_(x)—H,wherein x is an integer having the value of at least 8 and y is aninteger having the value of at least 38.

If a non-ionic polyoxyethylene-polyoxypropylene block copolymer is usedas an excipient, its contents in the overall composition may be betweenabout 0.01 mass % and about 20.0 mass %, such as between about 1.0 mass% and about 15 mass %, for example, about 10.0 mass %.

One non-limiting example of a specific non-ionicpolyoxyethylene-polyoxypropylene block copolymer that can be used as asolubilizing and stabilizing agent in the pharmaceutical compositions ofthe instant invention is the product known under the trade namePoloxamer 407® (poly(ethylene glycol)-block-poly(propyleneglycol)-block-poly(ethylene glycol)) available from Sigma-Aldrich Corp.of St. Louis, Mo., with the molecular weight of the polyoxypropyleneportion of about 4,000 Daltons, about a 70% polyoxyethylene content, theoverall molecular weight of between about 9,840 Daltons and about 14,600Daltons and having the following chemical structure

According to further embodiments, the excipient portion of thepharmaceutical formulation may contain other products, instead of, or incombination with, non-ionic polyoxyethylene-polyoxypropylene blockcopolymer(s). One non-limiting example of such additional excipient ispoly(acrylic acid) in its various cross-linked or non-cross-linkedversions, such as Carbomer 940® having a weight-average molecular weightof about 940 and available from Lubrizol Corp. of Wickliffe, Ohio.Another type of product that can be used in the excipient portion of thepharmaceutical formulation may be water-soluble methylcellulose andhydroxypropyl methylcellulose polymers, such as METHOCEL® family ofproducts available from Dow Chemical Co. of Midland, Mich., for example,a hydroxypropyl methylcellulose product METHOCEL® E4M.

According to further embodiments, methods for fabricating theabove-described pharmaceutical compositions are provided. A one-batchformulation method may be used, where the components of thepharmaceutical formulation can be combined in single container; thecomponents may be added to the container simultaneously orconsecutively. Alternatively, a two- or multiple-batch method(s) may beused if desired, where each component of the pharmaceutical formulationcan be combined in separate container followed by combining the contentsof each container.

In one exemplary, non-limiting procedure, a quantity of a tumor necrosisfactor inhibitor such as pentoxifylline may be placed into a mixingcontainer followed by adding a quantity of sterile water and a polymericgel (e.g., a Poloxamer 407®-based gel); the mixture is stirred until aclear stable solution is obtained, allowing the formulation to remainclosed system thus preventing contamination and the loss of sterility.

The resulting product may then be transferred into single dose vials,capped, sealed, autoclaved and shaken until cool. Finally, a completesterility and endotoxin may be performed on the product according tocommonly used methods known to those having ordinary skill in the art.As mentioned above, in some embodiments, the pharmaceutical compositionscan be used for topical administration such as compositions formulatedand delivered to a patient as eye drops. The compositions may alsocontain some quantity of preservative(s) such as benzalkonium chloride,if desired.

It will be understood by those having ordinary skill in the art that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,gender, diet, and the severity of the particular ophthalmologicalcondition being treated.

It is additionally envisioned that in some embodiments pharmaceuticalformulations disclosed herein may be used in combination with otherproducts that are intended to improve tear production. Non-limitingexamples of such other products include artificial tears of any kind,e.g., those containing hyaluronic acid, carboxymethyl cellulose,hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropylcellulose and derivatives thereof. Those having ordinary skill in theart and desiring to use the combinations of the presently describedformulations with artificial tears may design the method ofadministering the combinations. For example, the presently describedformulations may be pre-mixed with artificial tears and thus the presentformulations may be administered simultaneously with artificial tears.Alternatively, consecutive administering without pre-mixing is alsoviable.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of pharmaceuticalcompositions, the container containing one of the above-describedpharmaceutical compositions and a device for topically administering theformulation (e.g., an eye dropper). An instruction for the use of thecomposition and the information about the composition are to be includedin the kit.

The following examples are provided to further elucidate the advantagesand features of the present invention, but are not intended to limit thescope of the invention. The examples are for the illustrative purposesonly. USP pharmaceutical grade products were used in preparing theformulations described below.

Example 1. Preparing a Pharmaceutical Composition No. 1

A pharmaceutical composition was prepared as described below. Thefollowing components were used in the amounts and concentrationsspecified:

-   -   (a) about 20.0 g of aqueous solution of Poloxamer 407®, at a        concentration of Poloxamer 407® of about 20.0 mass %;    -   (b) about 0.11 g of Carbomer 940® (a powder); and    -   (c) about 100.0 mL of sterile water for injection.

Poloxamer 407® and Carbomer 940® were thoroughly mixed with water, untilfully dissolved, the pH was adjusted to about 5.5 using sodiumhydroxide. The product was then refrigerated overnight, placed into avial and autoclaved followed by adding the preservative benzalkoniumchloride (at about 1:10,000 mass ratio) to form a stockPoloxamer/Carbomer gel to be used in further steps. Next, the followingproducts were used in the amounts and concentrations specified:

-   -   (d) about 1.0 g of pentoxifylline, at a concentration of about        1.0%;    -   (e) about 90 mL of the Poloxamer/Carbomer gel obtained as        described above; and    -   (f) about 9.0 mL of sterile water for injection.

Pentoxifylline was combined with the gel and water and the final productwas transferred into dropper bottles (10 mL size), capped and sealed.The product has an estimated shelf life of about 90 days when keptrefrigerated.

Example 2. Preparing a Pharmaceutical Composition No. 2

A pharmaceutical composition was prepared as described below. Thefollowing components were used in the amounts and concentrationsspecified:

-   -   (a) about 0.4 g of METHOCEL® E4M (a powder);    -   (b) about 0.2 g of Carbomer 940® (a powder); and    -   (c) about 100.0 mL of sterile water for injection.

The METHOCEL® E4M and Carbomer 940® powders were combined in a beaker,then water was added to allow hydrating overnight to form a solution,the pH was adjusted to about 5.0 using sodium hydroxide. The gel wasautoclaved and cooled followed by adding preservative benzalkoniumchloride (at about 1:10,000 mass ratio) to form a stock METHOCEL®E4M/Carbomer solution to be used in further steps. Next, the followingcomponents were used in the amounts and concentrations specified:

-   -   (d) about 1.0 g of pentoxifylline, at a concentration of about        1.0%;    -   (e) about 90 mL of the METHOCEL® E4M/Carbomer solution obtained        as described above; and    -   (f) about 9.0 mL of sterile water for injection.

Pentoxifylline was combined with the gel and water and the final productwas transferred into dropper bottles (10 mL size), capped and sealed.The product has an estimated shelf life of about 90 days when keptrefrigerated.

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

What is claimed is:
 1. A method for improving tear production in amammalian subject suffering from an insufficient secretion thereof,comprising administering to an eye of the subject a pharmaceuticalformulation comprising: (a) a therapeutically effective amount of atleast one compound selected from the group consisting of pentoxifylline,lisofylline, aminophylline, enprofylline, isbufylline and combinationsthereof, or a pharmaceutically acceptable salt(s), solvate(s) orhydrate(s) thereof; (b) a therapeutically effective amount of animmunosuppressant selected from the group consisting of cyclosporine,tacrolimus and combinations thereof; and (c) a pharmaceuticallyacceptable carrier or excipient comprising a non-ionicpolyoxyethylene-polyoxypropylene block copolymer, at a concentration ofbetween about 0.01 mass % and about 1.0 mass % of the entireformulation, thereby improving tear production in the subject.
 2. Themethod of claim 1, wherein the excipient further comprises a polymerselected from the group consisting of poly(acrylic acid),methylcellulose, hydroxypropyl methylcellulose and combinations thereof.3. The method of claim 1, wherein the pharmaceutical formulation furthercomprises an active agent selected from the group consisting of at leastone anti-bacterial agent, at least one antiviral medicament, at leastone antifungal medicament, at least one immunosuppressant andcombinations thereof.
 4. The method of claim 3, wherein theanti-bacterial agent is selected from the group consisting ofmoxifloxacin, gatifloxacin, nalidixic acid, oxolinic acid, piromidicacid, pipemidic acid, rosoxacin, enoxacin, fleroxacin, lomefloxacin,nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balofloxacin,levofloxacin, norfloxacin, ciprofloxacin, pazufloxacin, sparfloxacin,tosufloxacin, clinafloxacin, gemifloxacin, sitafloxacin, prulifloxacin,vancomycin, teicoplanin, telavancin, decaplanin, ramoplanin,azitromycin, gentamicin, tobramycin, amikacin, cefuroxime, mitomycin,neomycin, neosporin, amoebicides, polymyxin, clindamycin, bacitracin,chloramphenicol, erythromycin, natamycin, blephamide, sulfacetamide,sodium bicarbonate, povidone-iodine and combinations thereof.
 5. Themethod of claim 3, wherein the antiviral medicament is selected from thegroup consisting of idoxuridine, vidarabine and combinations thereof. 6.The method of claim 3, wherein the antifungal medicament is selectedfrom the group consisting of ketoconazole, fluconazole and combinationsthereof.
 7. The method of claim 1, wherein the concentration of thecompound in the formulation is between about 0.03 millimoles and about 3millimoles of the compound per 1 μL of the formulation.
 8. The method ofclaim 1, wherein the insufficient tear secretion is caused by a disease,syndrome or pathology selected from the group consisting ofkeratoconjunctivitis sicca, Stevens-Johnson syndrome, age-related dryeye, ocular cicatricial pemphigoid, neurotrophic ocular surface diseaseand blepharitis.
 9. The method of claim 8, wherein the disease iskeratoconjunctivitis sicca.
 10. The method of claim 1, furthercomprising administering artificial tears comprising hyaluronic acid,carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvinylalcohol, or hydroxypropyl cellulose, or derivatives thereof.
 11. Themethod of claim 10, wherein the administering of the formulationcomprising the at least one compound and of the artificial tears issimultaneous or consecutive.
 12. The method of claim 1, wherein theadministering of the formulation is topical.
 13. The method of claim 1,wherein the compound is pentoxifylline or a pharmaceutically acceptablesalt thereof.
 14. The method of claim 13, wherein the pharmaceuticalformulation is administered as eye drops.